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US8273739B2 - Method for the purification of mycophenolate mofetil - Google Patents

Method for the purification of mycophenolate mofetil Download PDF

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Publication number
US8273739B2
US8273739B2 US12/666,846 US66684608A US8273739B2 US 8273739 B2 US8273739 B2 US 8273739B2 US 66684608 A US66684608 A US 66684608A US 8273739 B2 US8273739 B2 US 8273739B2
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Prior art keywords
mpm
water
impurity
etoac
mpa
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Expired - Fee Related, expires
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US20100190785A1 (en
Inventor
Robertus Mattheus De Pater
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Centrient Pharmaceuticals Netherlands BV
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DSM Sinochem Pharmaceuticals Netherlands BV
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/89—Benzo [c] furans; Hydrogenated benzo [c] furans with two oxygen atoms directly attached in positions 1 and 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3

Definitions

  • the present invention relates to a method for the purification of mycophenolate mofetil.
  • MPA Mycophenolic acid
  • 6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, 6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid, C 17 H 20 O 6 , CAS 24280-93-1) is a compound with various advantageous properties.
  • MPA also displays antifungal, antiviral and antitumor properties and the compound has been used in the treatment of psoriasis and recently as immunosuppressant.
  • the 2-morpholinoethyl ester of MPA also known as mycophenolate mofetil (MPM, C 23 H 31 NO 7 , CAS 128794-94-5), is a prodrug of MPA and has similar advantageous properties.
  • MPM mycophenolate mofetil
  • MPM can be prepared by esterification of MPA with 2-morpholinoethanol.
  • U.S. Pat. No. 4,753,935 an acid halide condensation route has been described. This is a two-step process requiring toxic reagents for forming the halide of MPA and/or of 2-morpholinoethanol.
  • EP 649,422 B1 an improved route was disclosed concerning refluxing MPA with 2-morpholinoethanol in an inert organic solvent capable of azeotropic removal of water, without the use of additional reagents.
  • One of the major problems associated with the synthesis of MPM is the formation of unwanted impurities.
  • Impurity B C 29 H 42 N 2 O 9
  • MPA or an amine salt of MPA is esterified in a conversion with 2-morpholinoethanol.
  • esterification is carried out in a solvent, preferably at elevated temperatures.
  • the solvent used for esterification of MPA can be a solvent such as benzene and substituted benzenes like ethyl benzene, meta-xylene, ortho-xylene, para-xylene and toluene, chloroform, methylene chloride, ethers such as dialkyl ethers like dibutyl ether and diisopropyl ether, ketones such as acetone, cyclohexanone, cyclopentanone, dipropyl ketone, methylisobutyl ketone, methylpropyl ketone and mixtures of these solvents.
  • Preferred solvents are xylene, dibutyl ether and cyclohexanone.
  • the esterification is carried out under azeotropic separation of water and under use of an excess of 2-morpholinoethanol, for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.
  • 2-morpholinoethanol for instance 1.00 to 20 molar equivalents, preferably 1.01 to 10 molar equivalents, more preferably 1.02 to 5 molar equivalents, most preferably 1.03 to 3 molar equivalents, still most preferably 1.04 to 2 molar equivalents.
  • the present invention is most suitably carried out under refluxing conditions, also esterification reactions carried out at lower temperatures than the boiling point can be further optimized by the presence of the chelating agent.
  • esterification at a temperature below the boiling point are that equipment for condensing solvent vapors and returning these condensed vapors are no longer required and the energy input required to reach and maintain the boiling point, which normally is substantial, can be circumvented. Furthermore, formation of unwanted by-products generally is lower at lower reaction temperatures.
  • the method of the present invention for the preparation of mycophenolate mofetil comprises the steps of:
  • water-immiscible solvent refers to a solvent which, when mixed with water, forms a two-phase system and which dissolves in water to an extent that the resulting aqueous phase contains less than 10% by weight of the solvent, preferably less than 1% by weight of the solvent, more preferably less than 0.5% by weight of the solvent.
  • inorganic liquids such as silicone fluids and halocarbon liquids which meet the definition and which are included in the definition of “water-immiscible solvents”
  • the far more common and thus preferred “water-immiscible solvents” are organic solvents, especially solvents comprising hydrocarbons and/or halohydrocarbons.
  • Suitable water-immiscible solvents include C 4 to C 14 branched, cyclic, and straight chain saturated and unsaturated aliphatic hydrocarbons; C 6 to C 12 alkaryl hydrocarbons; and halohydrocarbons containing up to about 4 halogen atoms, especially chlorine, and from 1 to about 8 carbon atoms. It is also very suitable to employ mixtures of these materials or distillation fractions composed primarily of these materials.
  • representative water-immiscible solvents include suitable freons, carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, dichloropropane, and similar halohydrocarbons, n-pentane, n-hexane, cyclohexane, 2-methylpentane, hex-1-ene, benzene, n-heptane, methylcyclohexane, cyclopentanone, cyclohexanone, branched heptanes and heptenes, toluene, the normal and branched octanes and octenes, the xylenes, ethylbenzene, n-nonane and the branched nonanes, the various decanes, the dodecanes and like hydrocarbons, C 6 -C 7 , C 6 -C 8 and C 7 -C 8 naphth
  • Preferred water-immiscible solvents are the C 6 to C 8 hydrocarbons including aliphatics like n-hexane, cyclohexane, n-heptane and n-octane and fractions composed in substantial part by these aliphatics and the aromatics such as benzene, toluene, ethylbenzene, xylenes and fractions composed in substantial part by these aromatics.
  • the pH-value used in step (b) can be further optimized to combine minimal loss of product resulting from degradation with maximal extraction yield. It has been found that the pH-value should be between 1.0 and 3.0, preferably between 1.5 and 2.7, more preferably between 1.8 and 2.4 and most preferably between 2.0 and 2.2.
  • the pH-value used in step (d) can be further optimized to combine maximal reduction of Impurity B with maximal extraction yield of the desired MPM. It has been found that the pH-value should be between 3.0 and 5.0, preferably between 3.75 and 4.75, more preferably between 4.0 and 4.5 and most preferably between 4.2 and 4.3. It has been found that at the pH-ranges mentioned above there is an unexpected difference in extraction behaviour between MPM and Impurity B where the former appears to dissolve to a very large extent in the organic phase whereas the latter dissolves to a large extent in the aqueous phase.
  • MPA is used in the form of a salt.
  • Suitable salts are amines and alkali metal salts.
  • an acid should be present in a molar amount that is at least equal to that of the molar amount of the MPA alkali metal salt.
  • addition of acid is not mandatory, although acid can also be added in order to decrease conversion times and/or increase yields.
  • Suitable amine salts of MPA are, but are not limited to, salts from amines such as tert-butylamine, cyclohexylamine, dibenzylamine, N,N-diisopropyl-ethylamine, N,N-dimethylcyclohexylamine, N,N-dimethylisopropylamine, N-methyl-piperidine, morpholine, tert-octylamine, piperidine, iso-propylamine, N,N,N′,N′-tetra-methylbutylenediamine, N,N,N′,N′-tetramethylethylenediamine, tributylamine, triethyl-amine and tripropylamine.
  • Suitable alkali metal salts of MPA are salts from lithium and potassium, preferably from sodium.
  • esterification of MPA or an MPA salt can be positively influenced (i.e. reduction of reaction time, increase of maximum conversion) by the addition of substances that are capable of absorbing water.
  • substances that are capable of absorbing water can be present in the mixture of MPA, solvent and 2-morpholinoethanol. However, these substances may also be present in the vapor phase of said mixture; despite the fact that the present invention deals with a method for esterification in non-boiling mixtures, a vapor phase nevertheless is usually present above such non-boiling mixtures.
  • Substances that are capable of absorbing water are for instance salts of alkali and earth alkali metals and usually these salts are carbonates, halides or sulfates.
  • Suitable examples are CaCl 2 , CaSO 4 , K 2 CO 3 , K 2 SO 4 , MgSO 4 , Na 2 CO 3 , Na 2 SO 4 and the like.
  • Preferred other substances are molecular sieves, preferably those with pore sizes ranging from 0.1-0.6 nm, more preferably ranging from 0.2-0.5 nm, most preferably ranging from 0.3-0.4 nm.
  • MPM is obtained according to the method of the first aspect.
  • Said MPM contains less than 0.05% by weight of Impurity B, preferably between 0.001% and 0.03% by weight of Impurity B, more preferably between 0.002% and 0.02% by weight of Impurity B, most preferably between 0.005% and 0.01% by weight of Impurity B.
  • MPM obtainable according to the first aspect can be used in pharmaceutical compositions, for instance in antifungal, antiviral and/or antitumor compositions, but also in compositions useful in the treatment of psoriasis and as immunosuppressant. Accordingly, said pharmaceutical compositions have the advantage that the amounts of Impurity B present in said compositions are at hitherto unprecedented low levels.
  • HPLC analysis was performed on a Waters HPLC ⁇ MS system (Alliance HT 2795 separation module; Diode array detector, model 996) with the following specifics:
  • Injection volume 5 ⁇ l (use fixed loop)
  • Mobile phase B Sörensen buffer/ACN (30/70)
  • the chemicals are water (Milli-Q purified or HPLC grade), acetonitrile (ACN, gradient grade, Merck 1.00030), KH 2 PO 4 (p.a., Merck 1.04873), Na 2 HPO 4 .2H 2 O (p.a., Merck 1.06580).
  • MPA-TEA MPA-Triethylamine Salt
  • Example 2 The reaction mixture obtained in Example 1 (60 ml) was diluted with water (60 ml). Under stirring the pH was adjusted to 2 with 6N H 2 SO 4 at 12 ⁇ 3° C. The phases were separated. The aqueous phase was extracted three times with EtOAc (40 ml) at pH 2.2 at 12 ⁇ 3° C. in order to remove unconverted MPA. The aqueous phase was divided into six portions of 20 ml. To each portion EtOAc (40 ml) was added and the pH of the six mixtures was adjusted to 3.5, 3.75, 4.0, 4.25, 4.5 and 5.0, respectively using 4N NaOH at room temperature. The phases were separated, giving EtOAc phases 1 and water phases 1; these phases were analyzed by HPLC.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 22.79 0 54.0 0 Water 1 46.31 0.67 46.0 1.45 EtOAc 2 19.61 0 79.4 0 Water 2 8.86 0.0145 20.6 0.16 At pH 3.5 Impurity B is not extracted into EtOAc. Yield MPM over first extraction is 54%. Yield loss over washing of the EtOAc-extract is 21%. MPM-yield over extraction and wash-step is 43%.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 35.69 0 84.2 0 Water 1 16.39 0.67 15.8 4.1 EtOAc 2 34.03 0 87.5 0 Water 2 8.42 0.0218 12.5 0.26 At pH 3.75 Impurity B is not extracted into EtOAc. Yield MPM over first extraction is 84%. Yield loss over washing of the EtOAc-extract is 13%. MPM-yield over extraction and wash-step is 74%.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 40.20 0.0213 94.4 0.05 Water 1 5.87 0.66 5.6 11.24 EtOAc 2 38.94 0 89.8 0 Water 2 7.39 0.0313 10.2 0.42 At pH 4.0 Impurity B is almost not extracted into EtOAc. The amount is below 0.1%. Yield MPM over first extraction is 94%. Yield loss over washing of the EtOAc-extract is 10%. MPM-yield over extraction and wash-step is 85%.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 39.79 0.035 97.5 0.09 Water 1 2.53 0.55 2.5 21.7 EtOAc 2 39.75 0 94.0 0 Water 2 4.40 0.0835 6.0 1.9 After extraction at pH 4.25 0.1% of Impurity B is found in the first EtOAc-extract. Yield MPM over first extraction is 98%. Yield loss over washing of the EtOAc-extract is 6%. MPM-yield over extraction and wash-step is 92%.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 43.30 0.086 98.3 0.20 Water 1 1.67 0.45 1.7 26.9 EtOAc 2 44.46 0 96.0 0 Water 2 3.22 0.158 4.0 4.9 After extraction at pH 4.5, 0.2% of Impurity B is in the first EtOAc-extract. Yield MPM over first extraction: 98%. Yield loss over washing of the EtOAc-extract: 4%. Impurity B can be reduced to ⁇ 0.1% by this step. MPM-yield over extraction and wash-step is 94%.
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (%) EtOAc 1 41.54 0.225 99.3 0.54 Water 1 0.77 0.121 0.7 15.7 EtOAc 2 43.18 0.225 99.4 0.52 Water 2 0.44 0.0438 0.6 9.9 After extraction at pH 5.0, 0.5% of Impurity B is found in the first EtOAc-extract. Yield MPM over first extraction is 99%. Yield loss over washing of the EtOAc-extract is 1%. After this wash-step 0.5% Impurity B is found in the extract. MPM-yield over extraction and wash-step is 99%.
  • Example 2 The reaction mixture obtained in Example 1 (60 ml) was diluted with water (60 ml). Under stirring the pH was adjusted to 2 with 6N H 2 SO 4 (4.7 ml) at 12 ⁇ 3° C. The phases were separated and the aqueous phase was extracted three times with EtOAc (3 ⁇ 40 ml) at pH 2.1 at 12 ⁇ 3° C. EtOAc (160 ml) was added to the water phase and the pH was adjusted to 4.25 with 4N NaOH (8.3 ml). The phases were separated and were analyzed by HPLC (water phase 1 and EtOAc phase 1). The EtOAc phase was washed with 80 ml water at pH 4.5 (pH adjustment with 20 ⁇ l 6N H 2 SO 4 ).
  • MPM Impurity B Yield MPM Impurity B/MPM Phase (g/l) (g/l) (%) (w/w %) EtOAc 1 63.0 48 97.4 0.08 Water 1 3.87 680 2.6 17.6 EtOAc 2 63.7 15 98.4 0.02 Water 2 2.02 55 1.6 2.7 EtOAc 3 66.3 21 99.4 0.03

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US12/666,846 2007-06-27 2008-06-24 Method for the purification of mycophenolate mofetil Expired - Fee Related US8273739B2 (en)

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EP07111199 2007-06-27
EP07111199 2007-06-27
EP07111199.1 2007-06-27
PCT/EP2008/058021 WO2009000834A1 (fr) 2007-06-27 2008-06-24 Procédé de purification de mycophénolate mofétil

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150203506A1 (en) * 2012-07-24 2015-07-23 Laurus Labs Private Limited Process for preparation of darunavir

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102924413B (zh) * 2012-10-23 2014-12-31 福建科瑞药业有限公司 一种霉酚酸莫啡酯纯化脱色方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
US5247083A (en) 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
WO2002100855A1 (fr) 2001-06-08 2002-12-19 Ivax Corporation Methode de preparation de mofetilmycophenolate
US20040167130A1 (en) 2003-02-21 2004-08-26 Kwang-Chung Lee Process for making mycophenolate mofetil by transesterification

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4753935A (en) * 1987-01-30 1988-06-28 Syntex (U.S.A.) Inc. Morpholinoethylesters of mycophenolic acid and pharmaceutical compositions
US5247083A (en) 1992-07-10 1993-09-21 Syntex (U.S.A.) Inc. Direct esterification of mycophenolic acid
WO2002100855A1 (fr) 2001-06-08 2002-12-19 Ivax Corporation Methode de preparation de mofetilmycophenolate
US20040167130A1 (en) 2003-02-21 2004-08-26 Kwang-Chung Lee Process for making mycophenolate mofetil by transesterification

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
International Search Report for PCT/EP2008/058021, mailed Dec. 2, 2008.

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150203506A1 (en) * 2012-07-24 2015-07-23 Laurus Labs Private Limited Process for preparation of darunavir
US9475821B2 (en) * 2012-07-24 2016-10-25 Laurus Labs Private Limited Process for preparation of Darunavir
US10214538B2 (en) 2012-07-24 2019-02-26 Laurus Labs Ltd. Process for preparation of Darunavir
US10544157B2 (en) 2012-07-24 2020-01-28 Laurus Labs Limited Process for preparation of Darunavir

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WO2009000834A1 (fr) 2008-12-31

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